Li Xinxin, Han Mengzhen, Zhu He, Pan Yonglong, Su Chen, Liu Yachong, Liao Zhibin, Zhang Bixiang, Chen Xiaoping
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.
Adv Sci (Weinh). 2025 Jul;12(27):e2504187. doi: 10.1002/advs.202504187. Epub 2025 Apr 26.
The transmembrane and coiled-coil domains 3 (TMCO3) are highly expressed in many tumors. However, the underlying mechanisms governing the way in which TMCO3 affects the progression of hepatocellular carcinoma (HCC) remain unclear. This study screens out the molecule TMCO3 with high N6-methyladenosine (mA) modification level in tumor samples compared to the adjacent non-cancerous tissues of three pairs of HCC patients through Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). Subsequently, the oncogenic effect of TMCO3 in HCC is verified through in vivo and in vitro experiments. AlkB Homolog 5 (ALKBH5), an mA demethylase of TMCO3 is then screened out. The following experiments demonstrate that TMCO3 can activate AKT directly through the Phosphatidylinositol-3-Kinase (PI3K) pathway, thus promoting the progression of HCC. Meanwhile, the phosphorylation site on TMCO3: the 85 amino acid-serine, and mutation of this site can directly impair the activity and membrane translocation of AKT is found. Finally, the carcinogenic effect of TMCO3 is further elucidated in HCC through the orthotopic treatment model and the hydrodynamic tail vein injection treatment model. The findings can provide a potential target for targeted AKT treatment in patients with HCC and verify a possible prognostic marker in HCC.
跨膜卷曲螺旋结构域蛋白3（TMCO3）在许多肿瘤中高表达。然而，TMCO3影响肝细胞癌（HCC）进展的潜在机制仍不清楚。本研究通过甲基化RNA免疫沉淀测序（MeRIP-seq）和RNA测序（RNA-seq），筛选出三对HCC患者肿瘤样本中与相邻癌旁组织相比具有高N6-甲基腺苷（m⁶A）修饰水平的分子TMCO3。随后，通过体内和体外实验验证了TMCO3在HCC中的致癌作用。接着筛选出TMCO3的m⁶A去甲基化酶AlkB同源物5（ALKBH5）。以下实验表明，TMCO3可通过磷脂酰肌醇-3-激酶（PI3K）途径直接激活AKT，从而促进HCC的进展。同时，发现TMCO3上的磷酸化位点：第85位氨基酸丝氨酸，该位点的突变可直接损害AKT的活性和膜转位。最后，通过原位治疗模型和尾静脉注射水动力治疗模型进一步阐明了TMCO3在HCC中的致癌作用。这些发现可为HCC患者靶向AKT治疗提供潜在靶点，并验证HCC中一种可能的预后标志物。
